Long-term follow-up reveals sustained benefit of dual CD19/CD22 CAR T-cell therapy alone or combined with autologous stem cell transplantation in TP53-altered relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract Introduction TP53 alterations are recognized molecular markers of high-risk disease in patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL), frequently associated with chemotherapy resistance and poor clinical outcomes. The prognostic impact of TP53 mutations in the context of chimeric antigen receptor (CAR) T-cell therapy remains insufficiently characterized, particularly with long-term follow-up. Dual-target CAR-T cell strategies such as CD19 and CD22 co-targeting, when combined with autologous stem cell transplantation (ASCT), may improve efficacy by preventing antigen escape and enhancing CAR-T cell persistence. However, comprehensive long-term data in this molecular subgroup remain limited. Methods We conducted a long-term follow-up study with a median duration of 77.8 months involving 122 patients with R/R aggressive B-NHL. Patients received CD19 and CD22 dual-target CAR-T cell therapy either as monotherapy (Trial A, n = 65) or in sequence with ASCT (Trial B, n = 57). TP53 mutation status was determined by genomic analysis. Clinical outcomes assessed included overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), immune reconstitution, and late adverse events. Prognostic factors were evaluated using multivariate Cox regression models. Results TP53 alterations were identified in 59 patients (48.4%). Within both cohorts, overall survival (OS) and progression-free survival (PFS) did not significantly differ between TP53-altered and wild-type subgroups (P > 0.05). Notably, the sequential ASCT-CAR-T approach (Trial B) was associated with substantially improved 5-year OS (70.2% vs. 40.0%) and PFS (64.9% vs. 35.4%) compared to CAR-T monotherapy. The 5-year cumulative incidence of non-relapse mortality was 15.2% overall (15.89% in Trial A vs. 14.43% in Trial B). Secondary malignancies occurred in 2.5% of patients, while serious infection-related events beyond three months post-infusion were observed in 13.6%, supporting a favorable longterm safety profile. Multivariate analysis identified treatment group (OS: HR 2.06, P = 0.036; PFS: HR 1.82, P = 0.072), not reaching remission at 3 months (NRR3; OS: HR 38.00, P < 0.001; PFS: HR 33.09, P < 0.001) and bulky disease (OS: HR 1.87, P = 0.019; PFS: HR 1.79, P = 0.024) as independent adverse prognostic factors for OS and PFS. Conclusions This long-term study demonstrates that dual-target CD19/CD22 CAR-T therapy, particularly when combined with ASCT, provides durable disease control with manageable toxicity in TP53-mutated r/r aggressive B-NHL. The comparable survival between TP53-mutant and wild-type patients within each arm suggests that this approach may overcome the historically adverse prognostic impact of TP53 alterations. NRR3 emerged as a strong early predictor of long-term outcome. These findings support the integration of dual-target CAR-T therapy with ASCT as a promising strategy for high-risk B-NHL and highlight the need for molecularly stratified therapeutic approaches in the era of precision immunotherapy.